The controlled release of an active ingredient from a pharmaceutical form containing it, is well known in the art. Generally, said systems contain one or more excipients which modulate the release acting as disgregating agents or as solubilizers, wetting agents etc., and/or one or more polymeric materials acting as excipients or barriers limitating the release and capable to control the release rate of the therapeutic agent. Said excipients should be logically compatible with the active ingredients and the administration site, stable in the action site, capable to interact with the active ingredient and the biologic fluids so as to provide the desired release control. They should be also easy available and not expensive. It is thus evident that the search for excipients always more sophisticated and adaptable to the different requirements is not presently ended. This is due both to the diversity and sometime complexity of the drugs to be used, and to the desire to obtain pharmaceutical forms even more sophisticated and reliable.
Thus in U.S. Pat. No. 2,828,206 discrete, free flowing particles are described, each comprising at least one inner core of fat-soluble vitamin material, said core being coated with a shell of a fat-insoluble substance selected from the group consisting of protein, gums, carbohydrates and pectin, which is in turn coated with a member of the group consisting of fats and waxes having a melting point between 45.degree. and 95.degree. C.
GB-A-1,044,572 claims a pharmaceutical composition providing prolonged release of a drug in the gastro-intestinal tract comprising a multitude of medicinal pellets randomly coated with a fatty acid coating comprising a saturated fatty acid or mixture of saturated fatty acids having from 12 to 22 carbon atoms per molecule, said coating being modified by an inert dusting powder which serves to form channels or pores through the otherwise continuous coating.
In U.S. Pat. No. 4,341,759 granules containing a pharmaceutically active material and at least one pharmaceutically inactive release controlling component are described, wherein said granules have a core and an outer layer comprising at least one active compound and at least one inactive release controlling substance over a period of time sufficient to cause said unitary layer to form on each core to give granules of size 0.3-2 mm.
U.S. Pat. No. 4,572,833 relates to a method for preparing a pharmaceutical oral controlled release composition, in which individual units comprise units of an active substance which is subject to controlled release as a result of coating the units with a substantially water--insoluble but water-diffusable controlled release coating comprising applying, on units comprising the active substance, a film-coating mixture comprising a solvent, a film-forming substance dissolved in the solvent and a hydrophobic substance substantially micro-dispersed in the film-coating mixture in a molten, but undissolved state, the film-coating mixture being applied at a temperature above the melting point of the hydrophobic substance.
U.S. Pat. No. 3,078,216 describes an oral pharmaceutical preparation having a prolonged release comprising a plurality of medicament granules, substantially all being from 12 mesh to 80 mesh, each coated with a layer of water insoluble, partly digestible hydrophobic material, the thickness of coating varying directly with particle size whereby in oral use the very fine granules rapidly release their medicament and the granules of increasing size release their medicament more and more slowly.
In U.S. Pat. No. 3,922,339 a process of preparing a sustained release pharmaceutical preparation of a medicament is described, which comprises (1) blending a medicament with desired inert materials, (2) wetting the blend with sufficient liquid material so as to act as a binder on compacting, (3) compacting the wetted blend by extruding to form a spaghetti-like material, (4) drying, breaking and screening the extruded material to the desired particle size, (5) spraying the particles with a solution of a film-forming material, (6) dusting the sprayed particles with a powder and drying to form a seal on the particles, and (7) coating the sealed particles with a solution of an excipient so as to form an enteric-soluble coating on the sealed particle.
From U.S. Pat. No. 3,432,593 a granule, capsule or tablet is known, having the active medicament adsorbed on a complex colloidal magnesium aluminum silicate. The individual granules may be further provided with one or more suitable retardant coatings, each of which provides a predetermined period of sustainment.
Further details concerning the preparation of pharmaceutical forms with controlled release of the active substance are reported for example in U.S. Pat. Nos. 3,137,630 and 8,492,397 as well as in EP-A-123,470.
From what stated above, it is clear that the controlled release technique has been widely used and studied, but the attempts to effect new improvements thereon go on unceasingly. Generally, the methods utilized for having suitable matrices inglobating the active ingredient are: compaction with pressure, granulation, extrusion and the film-forming procedure.
However, each of the above mentioned methods has many disadvantages. So dry compaction is possible only with suitable materials, requires the use of specific excipients which not always are compatible with the possible therapeutic uses, and is quite complex, requiring rather expensive apparatus. The wet granulation exposes the drug and the excipients to the deleterious water and heat action, is long and expensive and normally requires the use of binders that could interfere with the biodisponibility of the drug.
Also the film-forming procedure exposes the active ingredient and the excipients to the deleterious action of heat, water or other solvents; it needs long time and is expensive. Extrusion is then possible only with materials able to assume a plastic consistency with heat and submits thus the active ingredient and the excipient to a prolonged and potentially deleterious heating.
There at least to note that in the controlled release pharmaceutical forms the release kinetic is not always optimal. Often said release is in fact too slow or too rapid, that is not controlled. Said dosage forms are thus not free from problems, in that the need a high administration rate and can cause high fluctuations of drug in ematic and tissue concentrations and toxic effects arising from overdosage, with onset of the risk of severe side effects. In other cases a deficient therapeutic efficacy can be observed, arising from an insultable release kinetic or from a low user's compliance, that is from the non-taking of the drug when said taking is too frequent, unpleasant for the patient or causes negative side effects due to high peaks of ematic concentration of the drug.
Attempts have been made to solve at last partly all these problems employing ultrasonic energy. Thus in EP-A-0 467 743 a process for compacting a powder mixture is described, in which a non-thermoplastic product is blended with a thermoplastic one and the mixture thus obtained is submitted to ultrasonic energy with pressure. An adsorbing tablet is thus formed that can be imbued with a perfume and applied on the skin, or an adsorbing strip which can be imbued with a drug.
In U.S. Pat. No. 4,657,543 a process for delivering a biologically active substance on a demand is described, said process comprising the steps of combining a biologically active substance with a biocompatible polymeric composition as an admixture, forming said admixture into a shaped, solid polymeric matrix, implanting said solid polymeric matrix in vivo at a preselected site such that said solid implanted matrix is in a liquid environment, and exposing said implanted solid polymeric matrix to ultrasonic energy for a predetermined time to effect cavitation of said solid polymeric matrix by rapid compression with subsequent expansion of liquid or solid surrounding said solid polymeric matrix thereby to control the rate of release of said biologically active substance from said matrix over a specific time period wherein the rate of release is changed during said time period.
From U.S. Pat. No. 4,779,806 a process for delivering a composition on demand is at last known, which comprises incorporating said composition within a polymeric matrix, surrounding said composition and polymeric matrix with a liquid medium, and exposing said polymeric matrix to ultrasonic energy for a predetermined time and at a frequency to effect cavitation of said polymeric matrix to release said composition from said matrix in a controlled manner over a specific time period.
In all the literature mentioned above, with controlled release of a drug almost always a delayed release is meant, that is a release that permits the drug to be released slowly to the body. In both the last mentioned US patents use was then made ultrasonic energy for having cavitation of a polymeric matrix, but also in this case a delayed release is achieved and it is necessary to implant a matrix in vivo and to degrade the matrix for having the desired release. It is also known that cavitation exhibits a few disadvantages, the main of which is a loss of efficiency and risk for the health